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Sequencing Initiative Identifies New Lung Cancer Targets

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A major cancer sequencing initiative has identified new potential therapeutic targets for squamous cell lung cancer (SCLC), and provided data that will hopefully help scientists unpick the genetic basis of the disease and understand the pathways that lead to its initiation and progression. The Cancer Genome Atlas Project (TGCA) sequenced the protein-coding regions of 178 squamous cell carcinoma tumors and normal tissue from the same patients, as well as the whole genomes of 19 tumors and normal tissue pairs, and an analysis of tumor RNA.

The work mapped a diverse range of genomic alterations, including chromosomal rearrangements and structural changes in noncoding, possibly regulatory regions. Interestingly, a number of these mutations are also found in head and neck squamous cell carcinomas, which adds further weight to emerging evidence that it may be more useful to classify cancers according to their genetic make-up rather than the primary organ they affect. “This reinforces something that we’ve been seeing in a lot of our cancer genomics work,” remarks Richard K. Wilson, Ph.D., director of the Genome Institute at Washington University. “It’s really less about what type of tissue the tumor arises in—lung, breast, skin, prostate—and more about what genes and pathways are affected.”

Among the known SCLC-related genes highlighted through the sequencing and analyses, the results showed that p53 was mutated in nearly every tumor, while 70–80% of patients exhibited p16 mutations. Overall, there were mutations or amplifications in three families of tyrosine kinase genes, and also, surprisingly, in the HLA-A gene. “To our knowledge, this is the first example of a tumor that has a genomic mechanism for evading an immune response," comments Matthew Meyerson, M.D., professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School, who is one of the co-leaders of this TCGA project. “This may be important in understanding the immune response to squamous cell carcinoma and also in envisioning how immune-regulatory therapy might be used for this disease.”

SCLC comes second only to the more prevalent lung adenocarcinoma in terms of types of cancers that kill the most patients every year. However, unlike lung adenocarcinoma, for which EGFR-targeting treatments are available, there are no approved drugs that specifically address the mutations causing SCLC. The TCGA consortium hopes their findings will open the way to the development of SCLC-targeting therapeutics, and potentially new trials of candidate drugs that are already sanctioned for other indications. “This study clearly shows that SCLC, like lung adenocarcinoma, is a cancer with diverse genomic causes, many of which are potentially susceptible to drug inhibition,” professor Meyerson adds. “This provides many new therapeutic opportunities for squamous cell carcinoma that would be suitable for clinical trials.”

The TCGA work represents the first comprehensive genomic characterization of CSLC as a cancer subtype. The consortium, which is funded by NIH, has previously reported on brain cancer glioblastoma, ovarian cancer, and colorectal cancer. This latest work on SCLC is reported in Nature, in a paper titled “The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers."

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